Use of a Design of Experiments approach for the optimisation of a microwave assisted Ugi reaction
Heather Tye* and Mark Whittaker
*Evotec OAI, Milton Park, Abingdon, Oxfordshire, UK OX14 4SD, Email:
heather.tyeevotecoai.com
H. Tye, M. Whittaker, Org. Biomol. Chem., 2004, 2, 813-815.
DOI: 10.1039/b400298a
Abstract
The utility of a Design of Experiments (DoE) approach for the rapid and efficient optimisation of a microwave assisted Ugi 3cc reaction of levulinic acid with a range of amine and isonitrile substrates has enabled the preparation of lactam derivatives in moderate to excellent yields in a reaction time of only 30 min compared to the conventional methodology which required up to 48 h.
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Details
The study demonstrates the use of a Design of Experiments (DoE) approach to optimize a microwave-assisted Ugi 3cc reaction of levulinic acid, significantly reducing reaction time from 48 hours to just 30 minutes. Researchers Heather Tye and Mark Whittaker employed the MODDE 7™ software to design screening reactions, identifying key factors such as microwave reaction time, temperature, concentration, and amine equivalents. The optimal conditions were determined to be 1.5 equivalents of amine at 0.2 M concentration in methanol, irradiated at 100°C for 30 minutes, yielding the desired product in 90% yield. The study further explored the reaction's scope with various amine and isonitrile substrates, achieving moderate to excellent yields (17-90%). The reproducibility of the procedure was generally good, though variability was noted with ethyl isocyanoacetate substrates, indicating a need for further optimization. The research highlights the efficiency of DoE in rapidly optimizing microwave-assisted reactions and assessing their scope, providing a robust method for synthesizing Ugi adducts in significantly reduced timeframes.
Key Words
Ugi Reaction, Microwave Synthesis, Multicomponent Reactions, γ-Lactams
ID: J52-Y2004-210